The current study proposes to evaluate the nicotinic receptor antagonist mecamylamine (Inversine®) in comparison to matching placebo, in the treatment of depressive symptoms in smokers and non-smokers with major depressive disorder. These subjects would be maintained on antidepressant treatment with serotonin-selective reuptake inhibitors, and continue to exhibit at least mild depressive symptoms (e.g. partial antidepressant responders). The primary outcome measure will be depressive symptoms at the end of the 12-week trial (e.g. a 50% decrease in depressive symptoms) compared to baseline. Furthermore, we will compare the effects of mecamylamine versus placebo on smoking behavior in these SSRI-maintained partial responders.